PROJECT SUMMARY Tobacco smoking is associated with 480,000 deaths yearly; however, the currently approved treatments such as nicotine replacement therapies (NRTs) fail more than 70% of the time. Thus, more effective therapeutics for tobacco addiction are needed. Electronic cigarettes (ECs) are novel products that heat and aerosolize nicotine without combustion, seem to be less toxic than tobacco smoke, and have gained popularity with tobacco smokers as well as tobacco nave individuals. However, it is not known whether ECs provide effective nicotine delivery to the brain and arterial blood in smokers, and thus whether ECs would be an effective smoking cessation tool for tobacco smokers. The proposed research will test the overall hypothesis that ECs provide efficient nicotine delivery to the brain and arterial blood in EC-nave smokers and that the EC device electrical power modulates this effect. We will test this hypothesis through complementary methods that include positron emission tomography (PET) neuroimaging of brain beta2 nicotinic acetylcholine receptors (?2*-nAChRs), arterial blood nicotine measurements, and subjective drug effects. These findings will ultimately allow us to develop a clinical trial to determine feasibility of EC use for smokers in real-world treatment settings. In Aim 1, we will use [18F]Flubatine PET neuroimaging to assess ?2*-nAChR occupancy during high and low power EC use. In Aim 2, we assess arterial blood nicotine levels after EC use. In Aim 3, we will determine whether EC use can modify craving, liking, and withdrawal symptoms after a period of smoking abstinence. The project will determine whether ECs provide adequate brain nicotine delivery and the degree to which they can substitute tobacco smoking. This knowledge may result in the development of nicotine-based therapeutics for smokers that could save lives. The above study integrates nicely with the candidate's training proposal to become a physician-scientist. Dr. Baldassarri has assembled a comprehensive training plan and an expert team of mentors and advisors. Dr. Esterlis (mentor) is a recognized leader in neuroimaging and will provide expertise in PET studies. Dr. Bernstein (co-mentor) is a world expert in conducting clinical trials in tobacco control interventions and will provide expertise in trial design. Further expertise and guidance will be provided by world-renowned researchers in PET data analysis (Carson), regulatory science (Dr. O'Malley), nicotine pharmacology/ECs (Dr. Eissenberg), and biostatistics (Dr. Gueorguieva). Dr. Baldassarri will pursue advanced coursework in PET imaging, drug pharmacology, biostatistics, and clinical trial design. The combination of outstanding mentorship and the resources offered by the Yale PET Center and Yale Tobacco Center of Regulatory Science will prepare Dr. Baldassarri for a productive career as an independent investigator. Dr. Baldassarri will be ready to apply for an R01 by the 4th year of this award.